Impact of sex differences on the trajectory of interactome dysfunctions across the AD spectrum

性别差异对 AD 谱系中相互作用组功能障碍轨迹的影响

• 批准号: 10633261
• 负责人: GABRIELA CHIOSIS
• 金额: $ 118.91万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633261
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Autopsy; Bioinformatics; Biological; Biology; Brain; Brain region; Cells; Cerebellum; Chemicals; Clinical; Cognitive; Communities; Complex; Complex Analysis; Computational algorithm; Computer Analysis; Data; Data Analytics; Data Set; Defect; Dementia; Deposition; Development; Disease; Environment; Equipment and supply inventories; Freezing; Functional disorder; Generations; Genes; Genetic; Genotype; Global Change; Heterogeneity; Hippocampus; Hormonal; Human; Image; Impaired cognition; Individual; Knowledge; Knowledge Portal; Link; Maps; Measures; Metadata; Mining; Molecular; Nature; Nerve Degeneration; Neuroglia; Neurons; Online Systems; Outcome; Output; Pathologic; Pathway interactions; Patients; Phenotype; Phenotypic Sex; Positioning Attribute; Prevention; Process; Proteins; Proteome; Recording of previous events; Resources; Risk Factors; Sampling; Severities; Sex Differences; Site; Sorting; Specimen; System; Technology; Temporal Lobe; Testing; Time; Transcript; Translating; biological systems; brain cell; brain tissue; cell type; comorbidity; complex data; computerized data processing; connectome; data visualization; design; disease heterogeneity; disease phenotype; frontal lobe; functional outcomes; genome wide association study; healthy aging; innovation; insight; interest; invention; large scale data; laser capture microdissection; member; mild cognitive impairment; multidisciplinary; network dysfunction; neuropathology; novel strategies; open source; precision medicine; protein protein interaction; response; sex; spatiotemporal; stoichiometry; stressor; therapy development; user-friendly; web platform

ABSTRACT The impact of sex differences in Alzheimer's disease (AD) remains poorly understood, especially in the context of protein-protein interactions within vulnerable regions that drive dysfunction. Despite growing appreciation of the clinical course, presentation, and severity of AD, studies of sex impacting AD development and progression are lacking. Although recent high-throughput and bioinformatics technologies help to understand molecular and genetic basis of sex differences in aging and AD, reliance on static `omics data representing a descriptive inventory of biomolecules measuring changes in their stoichiometry at a given time and condition limits functional insights. Another roadblock is translating these complex datasets into biological insights requires sophisticated computational algorithms, diminishing access and impact to the biomedical community at large. To address these limitations this proposal introduces epichaperomics, an unbiased state-of-the-art `omics approach we invented to generate direct access to interactome perturbations and to the functional outcome of such changes in native biological systems. We posit by applying epichaperomics to well-characterized postmortem human brains that i) capture the disease trajectory, ii) encompass AD vulnerable and less affected regions, and iii) have robust parallel information on patient-specific correlates, will enable rigorous hypothesis- generating analyses on potential impact of stressors and vulnerabilities on disease trajectory, and on interactome as well as connectome dysfunctions as they occur in sex-dependent manner. Through this novel approach we expect to derive mechanistic innovation on specific dysfunctions impacted by sex differences leading to insights into sex-phenotype relationships not available through other `omics platforms. By evaluating, understanding, and anticipating interactome changes through epichaperome formation in relation to sex impact (Aim 1) and subsequent straightforward computational analysis with web-based output (Aim 2), first-of-a-kind proteome-wide insights into the impact of sex differences on interactome networks vulnerabilities and dysfunctions within the hippocampus and regions of the default mode network in relation to the relatively spared cerebellum, both on their nature and trajectory, in vulnerable cells and brain regions will be generated. Information how stressors and vulnerabilities (e.g., genes, environment, hormonal status) interact at cell and brain connectome levels to produce heterogeneous phenotype mapping of disease vulnerability will be produced. We posit a whole new treatment paradigm avenue will open, providing a previously unavailable sex-specific precision medicine approach to AD by understanding and targeting the interactome across the AD spectrum of no cognitive impairment, mild cognitive impairment, and AD dementia through stressor and vulnerability analysis. Raw datasets and data analytics from interactome network studies will be deposited into free-access portals accessible by the scientific community for additional mining and hypothesis testing studies. A web-based user- interface will also be designed facilitating data processing and visualization.

摘要

项目成果

Experimental traumatic brain injury increases epichaperome formation.

• DOI: 10.1016/j.nbd.2023.106331
• 发表时间: 2023-11
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Svirsky, Sarah E.;Li, Youming;Henchir, Jeremy;Rodina, Anna;Carlson, Shaun W.;Chiosis, Gabriela;Dixon, C. Edward
• 通讯作者: Dixon, C. Edward

Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system.

• DOI: 10.1038/s41467-021-24821-2
• 发表时间: 2021-08-03
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bolaender A;Zatorska D;He H;Joshi S;Sharma S;Digwal CS;Patel HJ;Sun W;Imber BS;Ochiana SO;Patel MR;Shrestha L;Shah SK;Wang S;Karimov R;Tao H;Patel PD;Martin AR;Yan P;Panchal P;Almodovar J;Corben A;Rimner A;Ginsberg SD;Lyashchenko S;Burnazi E;Ku A;Kalidindi T;Lee SG;Grkovski M;Beattie BJ;Zanzonico P;Lewis JS;Larson S;Rodina A;Pillarsetty N;Tabar V;Dunphy MP;Taldone T;Shimizu F;Chiosis G
• 通讯作者: Chiosis G

Proteomic profiling of interferon-responsive reactive astrocytes in rodent and human.

啮齿动物和人类干扰素反应性星形胶质细胞的蛋白质组学分析。

• DOI: 10.1002/glia.24494
• 发表时间: 2024
• 期刊: Glia
• 影响因子: 6.2
• 作者: Prakash,Priya;Erdjument-Bromage,Hediye;O'Dea,MichaelR;Munson,ChristyN;Labib,David;Fossati,Valentina;Neubert,ThomasA;Liddelow,ShaneA
• 通讯作者: Liddelow,ShaneA

Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action.

Zelavespib揭示了伴侣调制的机制：对目标占用和延长停留时间的生化见解。

• DOI: 10.3390/biomedicines11102599
• 发表时间: 2023-09-22
• 期刊: Biomedicines
• 影响因子: 4.7

Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer.

• DOI: 10.1038/s42003-021-02842-3
• 发表时间: 2021-11-25
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Joshi S;Gomes ED;Wang T;Corben A;Taldone T;Gandu S;Xu C;Sharma S;Buddaseth S;Yan P;Chan LYL;Gokce A;Rajasekhar VK;Shrestha L;Panchal P;Almodovar J;Digwal CS;Rodina A;Merugu S;Pillarsetty N;Miclea V;Peter RI;Wang W;Ginsberg SD;Tang L;Mattar M;de Stanchina E;Yu KH;Lowery M;Grbovic-Huezo O;O'Reilly EM;Janjigian Y;Healey JH;Jarnagin WR;Allen PJ;Sander C;Erdjument-Bromage H;Neubert TA;Leach SD;Chiosis G
• 通讯作者: Chiosis G